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Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

ISSN: 2231-3354 Orally disintegrating tablets : formulation, preparation Received: 12-06-2011 Revised : 17-06-2011 Accepted: 19-06-2011 techniques and evaluation

Priyanka Nagar, Kusum Singh, Iti Chauhan, Madhu Verma, Mohd Yasir,

Azad Khan, Rajat Sharma and Nandini Gupta

ABSTRACT

Oral delivery is currently the gold standard in the pharmaceutical industry where it is

regarded as the safest, most convenient and most economical method of delivery having the

Priyanka Nagar, Kusum Singh, Iti highest patient compliance. Formulation of a convenient for , by Chauhan, Madhu Verma, Mohd Yasir, considering swallowing difficulty especially in case of geriatric and pediatric patient leads to Azad Khan, Rajat Sharma and poor patient compliance. To troubleshoot such problems a new dosage form known as orally Nandani Gupta disintegrating (ODT), has been developed which rapidly disintegrate & dissolve in saliva Department of Pharmaceutics, and then easily swallowed without need of water which is a major benefit over conventional ITS College, dosage form. In addition, patients suffering from dysphasia, , repeated emesis Muradnagar, Ghaziabad, India and mental disorders prefer such preparation because they cannot swallow large quantity of water. Further, exhibiting satisfactory from the oral mucosa or intended for

immediate pharmacological action can be advantageously formulated in such type of dosage form. The popularity and usefulness of the formulation resulted in development of several ODT technologies for preparation. The current article is focused on ideal characteristics, advantages and disadvantages, formulation aspects, formulation technologies, evaluation of products and

future potential. Various marketed preparations along with numerous scientific advancements

made so far in this avenue have also been discussed.

Key words: API, Fast dissolving tablet, Oral route, , Oral dissolving tablet.

INTRODUCTION

Oral administration is the most popular route due to ease of , pain avoidance, versatility (To accommodate various types of drug candidates) and most importantly, patient

compliance (Sastry et al, 1997). Also, oral delivery systems do not require sterile conditions

and are, therefore, less expensive to manufacture (Fasano et al, 2005). A vast variety of

pharmaceutical research is directed at developing new dosage forms for oral administration. Most

of these efforts have focused on either formulating novel systems or increasing the patient compliance. Among the dosage forms developed for facilitating ease of , the

orally disintegrating systems have been the favorite of product development scientists. In similar fashion the oral cavity is highly acceptable by patients, the mucosa is relatively permeable with

rich blood supply and virtual lack of langerhans cells makes oral mucosa tolerant to potential *For Correspondence: allergens (Shojaei et al, 1998). Mr. Mohd Yasir (Assistant professor) Overview of Oral Mucosa H. No. 253, Ismail Nagar Under Kot, Meerut City-250001 (UP). India The anatomical and physiological properties of the oral mucosa have been extensively E-mail: [email protected] reviewed by several authors (Shojaei.et al, 1998 & Gandhi.et al, 1994). The oral cavity comprises

Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

the lips, cheek, tongue, hard palate, soft palate and floor of the decade, particularly for geriatric and pediatric patients who mouth (Fig. 1). The lining of the oral cavity is referred to as the experience difficulty in swallowing conventional tablets and oral mucosa, and includes the buccal, sublingual, gingival, palatal capsules. Hence, they do not comply with prescription, which and labial mucosa. The buccal, sublingual and the mucosal tissues results in high incidence of ineffective therapy (Seager et al, 1998) at the ventral surface of the tongue account for about 60% of the oral mucosal surface area. The top quarter to one-third of the oral mucosa is made up of closely compacted epithelial cells (Fig. 2). The primary function of the oral epithelium is to protect the underlying tissue against potential harmful agents in the oral environment and from fluid loss (Collins et al 1987). Beneath the epithelium are the basement membranes, lamina propia and submucosa. The oral mucosa also contains many sensory receptors including the taste receptors of the tongue. Three types of oral mucosa can be found in the oral cavity; the lining mucosa is found in the outer oral vestibule (the buccal mucosa) and the sublingual Fig.2: Schematic diagram of buccal mucosa (Smart et al, 2004) region (floor of the mouth) (Fig. 1). The specialized mucosa is found on the dorsal surface of tongue, while the masticatory Table1: The advantages and disadvantages associated with utilizing the oral mucosa is found on the hard palate (the upper surface of the mucosa as a drug delivery site (Sankar et al, 2011). mouth) and the gingival (gums) (Smart et al, 2004). Advantages Disadvantages The lining mucosa comprises approximately 60%, the 1. Accessible 1. Permeability barrier of the oral masticatory mucosa approximately 25%, and the specialized 2. Self administrable mucosa 3. Oral mucosa repairs rapidly 2. Saliva washes away drug mucosa approximately 15% of the total surface area of the oral 4. Different areas of the oral 3. Mastication and speech may mucosal lining in an adult human. The masticatory mucosa is cavity have different dislodge permeability characteristics 4. Delivery device located in the regions particularly susceptible to the stress and 5. Highly hydrated environment 5. Requires formulation for strains resulting from masticatory activity. The superficial cells of to dissolve drug agreeable taste the masticatory mucosa are keratinized, and a thick lamina propia 6. Sustained delivery possible 6. Highly enzymatic environment 7. Potential reduction of systemic 7. Relatively small surface area tightly binds the mucosa to the underlying periosteum. Lining side effects 8. Risk of choking on or mucosa on the other hand is not nearly as subject to masticatory 8. Avoid the hepatic first-pass swallowing delivery device effect loads and consequently, has a non-keratinized epithelium, which 9. High blood supply sits on a thin and elastic lamina propia and a sub mucosa. The 10. Fast systemic delivery possible mucosa of the dorsum of the tongue is a specialized gustatory mucosa, which has well papillated surfaces which are both In disease conditions such as motion sickness, sudden keratinized and some non-keratinized (Collins et al, 1987). Table 1 episodes of attacks of coughing and repeated emesis swallowing depicted the advantages and disadvantages associated with conventional solid dosage forms become difficult. Orally utilizing the oral mucosa as a drug delivery site. disintegrating dosage forms can serve as an effective alternative mode of drug delivery in such situations (Ghosh et al, 2005). When put in the mouth, these dosage forms disintegrate instantly to release the drug, which dissolves or disperses in the saliva (Dobetti et al, 2001). Thereafter, the drug may get absorbed from the and or from other sections of GIT as the saliva travels down. In such cases, is significantly greater than that observed from conventional tablet dosage form (Brown et al 2001 & Deepak et al, 2004). The novel technology of oral disintegrating dosage forms is known as fast dissolve, rapid dissolve, rapid melt and quick dispersible tablets (Gupta et al, 2010). However, the function and concept of all these dosage forms are similar. Different orally Fig. 1: Schematic representation of the different linings of mucosa in mouth disintegrating dosage forms are as follows: (Squier.et al, 2001)

ORALLY DISINTEGRATING DOSAGE FORMS 1. Orally disintegrating tablets: It is a tablet that dissolves or disintegrates in the oral cavity without the need of water or The concept of orally disintegrating dosage forms has (Gupta et al, 2010). emerged from the desire to provide patients with more 2. Fast dissolving films: The fear of taking solid tablets and the conventional means of taking their medication. Interestingly, the risk of choking for certain patient population still exists demand for ODDFs has enormously increased during the last despite their short dissolution and disintegration time. It Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

consists of very thin oral strip, which releases the active 3. Be compatible with taste masking. ingredient immediately after uptake in to the oral cavity. It 4. Be portable without fragility concern. combines all advantages of tablets along with dosage 5. Leave negligible or no residue in the mouth after oral forms. This system is simply placed on patients tongue or any administration. other mucosal surface, instantly wet by saliva; film rapidly 6. Exhibit low sensitivity to altered environmental conditions hydrates and dissolves to release the medication (Vollmer et such as humidity and temperature. al, 2007). 7. Allow high drug loading. 3. Fast Caps: A new type of fast disintegrating drug delivery 8. Adaptable and amenable to conventional processing and system based on capsules was developed. In contrast to packaging equipment at nominal expense. conventional hard gelatin capsules, the fast caps consist of gelation of low bloom strength and various additives to Advantages of ODTs improve the mechanical and dissolution properties of 1. ODT can be administer to the patients who cannot swallow shell. It includes several advantages like high drug loading, tablets/cap., such as the elderly, stroke victims, bedridden possible solid and liquid filling, and no compression of coated patients, patients with esophageal problems & patients who taste masked or extended release drug particles / pellets, good refuse to swallow such as pediatric, geriatric & psychiatric mechanical properties, simple manufacturing, mechanical patients and thus improves patient compliance (Wilson et al, stability and requirement of special packaging. (Bodmeier et 1987). al, 1999). 2. It contain the certain studies which concluded increased 4. Medicated chewing gums: it is an attractive alternative for bioavailability and proved rapid absorption of drugs drug delivery system with several advantages including through pregastric absorption of drugs from mouth, pharynx convenience for administration, mainly is used & esophagus as saliva passes down (Fix et al, 1998). to promising controlled release drug delivery system. These 3. ODT is most convenient for disabled, bedridden patients, are mainly available currently for pain relief, travelers and busy people, who do not always have access to cessation, travel illness and freshening of breath.(Pandit et al, water (Fix et al, 1998). 2006). 4. Good mouth feel property of ODT helps to change the 5. Freeze-dried wafer: it is a quick-disintegrating, thin matrix that of medication (Allen et al, 1997). contains a medicinal agent that does not need water for 5. As bitter pill particularly in pediatric patients (Wilson et al, swallowing. This fragile dosage form requires unit- 1987). packaging to ensure physical stability. The wafer disintegrates 6. The risk of chocking or suffocation during oral administration instantaneously in the oral cavity and releases drug, which of conventional formulations due to physical obstruction is dissolves or disperses in the saliva. The saliva is swallowed avoided, thus providing improved safety (Indurwade et al, and the drug is absorbed across the (GIT). 2000). (Dobetti et al, 2001). 7. ODT opened new business opportunity like product

differentiation, product promotion, patent extension and life ORALLY DISINTEGRATING TABLETS cycle management (Wilson et al, 1987). The performance of ODTs depends on the technology 8. Suitable during traveling where water may not be available used in their manufacture. The orally disintegrating property of (Fix et al, 1998). these tablets is attributable to the quick ingress of water into the 9. No specific packaging required can be packaged in push tablet matrix, which creates porous structure and results in rapid through blisters (Kuchekar et al, 2003). disintegration. Hence, the basic approaches to develop ODTs 10. Conventional manufacturing equipment (Kuchekar et al, include maximizing the porous structure of the tablet matrix, 2003). incorporating the appropriate disintegrating agent and using highly 11. Cost effective (Wilson et al, 1987). water-soluble excipients in the formulation (Wilson et al, 1987). 12. Good chemical stability as conventional oral solid dosage form (Allen et al, 1997). Ideal characteristics of ODTs 13. New business opportunity like product differentiation, product promotion, patent extension and life style management ODTs should depict some ideal characteristics to distinguish them (Wilson et al, 1987). from traditional conventional 14. Allow high drug loading (Fix et al, 1998). dosage forms. Important desirable characteristics of these dosage 15. Provides rapid drug delivery from dosage forms (Allen et al, forms include (Kuchekar et al, 2003) 1997). 1. No water requirement for swallowing purpose but it should 16. Provide advantage of liquid medication in form of solid dissolve or disintegrate in the mouth usually within fraction of preparation (Shyamala et al, 2002) seconds. 17. Rapid drug therapy intervention (Wilson et al, 1987) 2. Provide pleasant feeling in the mouth. 18. No chewing needed (Fix et al, 1998). Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

19. Adaptable and amenable to existing processing and packaging include neuroleptics, cardiovascular agents, analgesics, machinery(Wilson et al, 1987) antiallergic, anti-epileptics, anxiolytics, sedatives, hypnotics, 20. Rapid onset of action (Bradoo et al, 2001) diuretics, anti-parkinsonism agents, anti-bacterial agents and drugs used for erectile dysfunction (Kushekar et al, 2003) Disadvantages of ODTs In contrast, the following characteristics may render unsuitable for delivery as an orally disintegrating tablet:- 1. ODT is hygroscopic in nature so must be keep in dry place 1. Short half life and frequent dosing. (Devrajan et al, 2003) 2. Very bitter or otherwise unacceptable taste because taste 2. Some time it possesses mouth feeling (Chang et al, 2000). masking cannot be successfully achieved. 3. It is also shows the fragile, effervescence granules property 3. Require controlled or sustained release. (Chang .et al, 2000) 4. Combination with anticholinergics. 4. ODT requires special packaging for properly stabilization &

safety of stable product (Devrajan et al, 2003) B. Selection of excipients: Mainly seen excipients in ODT are as

follows at least one disintegrant, a diluent, a lubricant, and MECHANISMS OF ODTs optionally, a swelling agent, sweeteners, and flavoring agents etc. ODTs involve the following mechanisms to achieve the Ideal bulk excipients for orally disintegrating dosage forms should desired fast dissolving characteristics (Sahoo et al, 2010): have the following properties (Bansal et al, 2003):

1. Water must quickly enter into the tablet matrix to cause rapid 1. Disperses and dissolves in the mouth within a few seconds disintegration and instantaneous dissolution of the tablet. without leaving any residue. 2. Incorporation of an appropriate disintegrating agent or highly 2. Masks the drug’s offensive taste and offers a pleasant mouth water soluble excipients in the tablet formulation. feel. 3. There are some under mentioned mechanisms by which the 3. Enables sufficient drug loading and remains relatively tablet is broken down into the smaller particles and then unaffected by changes in humidity or temperature. subsequently result a or of the drug. The The role of excipients is important in the formulation of mechanisms are- fast-melting tablets. The temperature of the excipients should be  High swellability of disintegration preferably around 30–350C for faster melting properties. Detail of  Chemical reaction excipients is given in table 2 & 3.  Capillary action Table 2: Excipients to be used for the preparation of ODTs (Liang .et al, 2001)

FORMULATION ASPECTS OF ODTs Excipients Function Examples

Superdisintegrant Increases the rate of Crospovidone, Important ingredients that are used in the formulation of disintegration and hence the Microcrystalline , ODTs should allow quick release of the drug, resulting in faster dissolution. The presence of sodium glycolate, other formulation ingredients sodium carboxy methyl dissolution. This includes both the pharmacologically active such as water-soluble cellulose, pregelatinzed ingredients (drug) and the excipients (additives). excipients and effervescent starch, agents further hastens the Carboxy , A. Selection of drug candidate: Several factors may be considered process of disintegration. For and modified corn starch. while selecting an appropriate drug candidate for development of the success of fast dissolving Sodium starch glycolate has tablet, the tablet having good flowability than orally disintegrating tablets. The ultimate characteristics of a drug quick dissolving property crosscarmellose sodium. for dissolution in mouth and pregastric absorption from fast which is achieved by using Cross povidone is fibrous the super disintegrant nature and highly dissolving tablets include (Reddy et al, 2002) compactable Flavors Increases Patient compliance flavor, cooling 1. Free from bitter taste and acceptability flavor, flavor oils and flavoring aromatic oil, 2. Dose lower than 20mg peppermint oil, clove oil, bay 3. Small to moderate molecular weight oil, anise oil, thyme oil, oil of bitter 4. Good in water and saliva almonds. Flavoring agents 5. Partially unionized at oral cavity pH include, vanilla, citrus oils, fruit essences. 6. Ability to diffuse and partition in to the epithelium of upper Sweeteners and This is another approach to Artificial sweeteners like GIT(log >1,or preferably>2) based manufacture ODT by direct Aspartame, excipients compression. Sugar based derivatives. Bulking agents 7. Ability to permeate oral mucosal tissue. excipients acts as bulking like dextrose, , agents .These exhibits high isomalt, lactilol, , There are no particular limitations as long as it is a aqueous solubility and maltose, , , sweetness, and hence impart starch hydrolysate, substance which is used as a pharmaceutical active ingredient. taste masking property and a polydextrose and Researchers have formulated ODT for various categories of drugs pleasing mouth feel. Surface Active Reduces interfacial tension Sodiumdoecylsulfate, used for therapy in which rapid peak plasma concentration is agents and thus enhances sodiumlaurylsulfate, required to achieve the desired pharmacological response. These solubilization of FDT polyoxyethylene sorbitan fatty acid esters (Tweens), Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

sorbitan fatty acid esters et al, 1993). Detail of all these conventional techniques is given in (Spans), polyoxyethylene stearates. table 4. Maintains integrity of dosage (PVP),P form prior to administration olyvinylalcohl(PVA) Hydroxy propyl Patented Techniques methylcellulose(HPMC) Rapid-dissolving characteristic of ODTs is generally Color Enhances appearance and Sunset yellow, Amaranth, organoleptic properties of Red iron oxide attributed to fast penetration of water into tablet matrix resulting in dosage form its fast disintegration. Several technologies have been developed Lubricants Lubricant helps reduce Stearic acid, friction and wear by stearates, Zinc state, calcium on the basis of formulation aspects and different processes and introducing a lubricating state, talc, polyethylene resulting dosage forms vary on several parameters like mechanical film between mechanical glycol, liquid paraffin, moving parts of tablet magnesium lauryl sulfate, strength, porosity, dose, stability, taste, mouth feel, dissolution rate punching machine colloidal silicon dioxide. Fillers Enhances bulk of dosage Directly compressible spray and overall bioavailability. Table 5 represents the list of unique form dried Mannitol, Sorbitol, patented technologies, their advantages, disadvantages, and Table xylitol, , magnesium carbonate, 6 represents the patented technology and their branded products. calcium phosphate, calcium sulfate, pregelatinzed starch, EVALUATION OF ODTs magnesium trisilicate, Evaluation parameters of tablets mentioned in the aluminium hydroxide Pharmacopoeias need to be assessed, along with some special tests.

Table 3: Superdisintegrants to be used for the preparation of ODTs (Bhowmik.et al, The quality of tablet, once formulated by rule, is generally dictated 2009) by the quality of physicochemical properties of blends (Reddy et al, 2002). There are many formulation and process variables Name Composition Mechanism of Special comment action involved in mixing and all these can affect the characteristics of Crosscarmellose Cross linked -Swells 4-8 folds in -Swells in two blends produced (Kushekar et al, 2003). Ac-Di-Sol cellulose < 10 seconds. dimensions. Nymce ZSX -Swelling and -Direct A. Evaluation of blends before compression: The various Primellose®Solu wicking both. compression or tab granulation characteristics of blends to be tested before compression are Vivasol L-HPC -Starch free (Kushekar et al, 2003 & Shyamala et al, 2002): Crospovidone Cross linked Swells very little -Water insoluble Crospovidone M PVP And returns to and Kollidon original size after spongy in nature 1. Angle of repose: Angle of repose is determined by using funnel Polyplasdone compression but act so get method. The accurately weighed blend is taken in a funnel. The by capillary action porous tablet height of the funnel is adjusted in such a way that the tip of the Sodium starch Cross linked Swells 7-12 folds in -Swells in three glycolate starch < 30 seconds dimensions and funnel just touches the apex of the heap of blend. The drug (as Explotab high level serve as solid dispersion)- blend is allow to flow through the Primogel sustain release matrix funnel freely on to the surface. The diameter of the cone is Alginic acid NF Cross linked -Rapid swelling in -Promote measured and angle of repose is calculated using the following Satialgine alginic acid aqueous medium disintegration or wicking action in both dry or wet equation. granulation Soy Natural super -Does not contain Tan Ө = h/r disintegrant any Emcosoy starch or sugar. Where h and r are the height of cone and radius cone base Used in nutritional products respectively. Angle of Repose less than 30 ° shows the free Calcium silicate -Wicking Highly porous, flowing of the material. action Optimum concentration is Bulk density: Apparent bulk density is determined by pouring a between 20-40% weighed quantity of blend into graduated cylinder and measuring the volume and weight. Bulk density can be calculated by using TECHNIQUES FOR PREPARATION OF ODTs following formula: The techniques used to manufacture ODTs can be Bulk density = Weight of the powder / Volume of the packing. classified as:- 1) Conventional techniques Tapped density: It is determined by placing a graduated cylinder, 2) Patented techniques containing a known mass of drug-excipients blend. The cylinder is allowed to fall under its own weight onto a hard surface from the Conventional Techniques height of 10 cm at 2 second intervals. The tapping is continued The various conventional technologies are developed for until no further change in volume is noted. Tapped density can be the preparation of Orally Disintegrating drug delivery system that calculated by using following formula: are Freeze drying, Spray drying, Molding , Phase transition process, Melt granulation, Sublimation, Mass Extrusion, Cotton Tapped Density = (Weight of the powder / volume of the tapped packing) Process, Direct compression (Meyers et al, 1995 & Makino Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

Table 4: Conventional techniques used for the preparation of ODTs.

S.No Techniques Method and characteristics of prepared ODTs

1 Disintegrant Involves the addition of superdisintegrants in optimum concentration to the formulation to achieve rapid disintegration/dissolution. For e.g. addition MCC and sodium starch glycolate are used in formulation of , Crystalline cellulose (AvicelPH-102)and low substituted HPEC used in oxybutinin and pirenzepine formulation. Crospovidone used in galanthamine HBr. Crospovidone (3%w/w) and crosscarmellose Na (5%w/w) used in prochlorperazine maleate formulation. Characteristics: similar to conventional tablets with higher % of disintegrants, lower hardness and higher % of friability 2. Freeze Drying The drug is dissolved or dispersed in an aqueous solution of a carrier. The mixture is poured into the wells of the preformed blister packs. or The trays holding the blister packs are passed through liquid nitrogen freezing tunnel to freeze the drug solution. Then the frozen blister Lyophilization packs are placed in refrigerated cabinets to continue the freeze drying. Finally the blisters are packaged and shipped.

Characteristics: The preparations are highly porous, have high specific surface area, dissolve rapidly and ultimately show improved absorption and bioavailability. Dose incorporated:- insoluble 400mg Water soluble drug loading:- 60mg Advantages of Freeze drying  Tablets produced by this technique possess very low disintegration time.  Render tablets with great mouth feel due to fast melting effect.  Provides immediate dissolution (5 sec).  Increases absorption and bioavailability of drug.  Lyophilization is useful for heat a sensitive drug that is thermo labile substances.  Tablets prepared by lyophilization disintegration rapidly in less than 5 sec due to quick penetration of saliva in pores when placed in oral cavity. Disadvantages of freeze drying  Relatively expensive and time consuming process.  The product obtained is poorly stable and fragile, sensitive to humidity rendering conventional packaging unsuitable.  Very poor physical resistance,  High cost of production,  Low dose of water-soluble drugs 3 Moulding Water-soluble ingredients with a hydro alcoholic solvent is used and is molded into tablets under pressure lower than that used in conventional tablet compression. Characteristics: Molded tablets are very less compact than compressed tablet porous structure that enhances disintegration/dissolution and finally absorption increased. Advantages : Very rapid dissolution (5–15 s) Disadvantages : High cost of production , Weak mechanical strength Possible limitations in stability 4 Sublimation Inert solid ingredients that volatilize rapidly like , ammonium carbonate, ammonium bicarbonate, and hexamethylenetetramine were added to the other tablet ingredients and the mixture is compressed into tablets. The volatile materials were then removed via sublimation, which generates porous structure. Characteristics: Porous structure that enhances dissolution by using volatile material or solvent e.g. cyclohexane, benzene etc. Advantages: Good physical resistance & highly porous structure Disadvantages: Harmful residual adjuvant, Extra equipments for heating, Not applicable to volatile and heat sensitive drugs 5 Spray-Drying By hydrolyzed and non hydrolyzed as supporting agents, mannitol as bulking agent, sodium starch glycolate or crosscarmellose sodium as disintegrating agent and an acidic material (e.g. citric acid) and / or alkali material (e.g. Sodium bicarbonate) to enhance disintegration /dissolution.(Mishra DN.et al) Characteristics: Prepared tablet disintegrates within 20 seconds when immersed in an aqueous medium

6 Mass Involves softening the active blend using the solvent mixture of water soluble polyethylene glycol, methanol and expulsion of softened mass Extrusion through the extruder or to get a cylindrical shape of the product into even segments using heated blade to form tablets. Characteristics: The dried product can be used to coat granules of bitter tasting drugs and thereby masking their bitter taste.

7 Direct Conventional equipment, commonly available excipients and a limited number of processing steps are involved in direct compression. compression Characteristics: It is most cost effective tablet manufacturing technique. Advantages • Requires fewer unit operations compared with wet Granulation (shorter processing time and lower energy consumption)

• Fewer stability issues for actives that are sensitive to heat or moisture

• For certain compounds, faster dissolution rates may be generated from tablets prepared by direct compression compared with wet granulation; for example, Norfloxacin. • Fewer excipients may be needed in a direct compression Formula. Disadvantages • Issues with segregation – these can be reduced by matching • The particle size and density of the active drug substance with excipients • In general, the drug content is limited to approximately 30% or approximately 50 mg • Not suited for poorly flowing drug compounds • Static charges may develop on the drug particles or excipients during mixing, which may lead to agglomeration of particles producing poor mixing 8 Cotton candy Involves the formation of matrix of polysaccharides by simultaneous action of flash melting and spinning. This candy floss matrix is then process milled and blended with active ingredients and excipients after re-crystallization and subsequently compressed to FDT. Characteristics: It can accommodate high doses of drug and offers improved mechanical strength. 9 Compaction Prepared by incorporating a hydrophilic waxy binder (super polystate) PEG-6-stearate. Super polystate not only acts as binder and increase a) Melt physical resistance of tablet but also helps the disintegration of tablet. granulation Characteristics: It melts in the mouth and solubilizes rapidly leaving no residue. Prepared by compressing a powder containing two sugar alcohols with high and low melting points and subsequent heating at a temperature

between their melting points. The tablet hardness was increased after heating process due to increase of inter particle bond induced by phase b) Phase- transition of lower melting point . transition Characteristics: The compatibility increased and so sufficient hardness gained by the formulation. process

Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

10 Nanonization Involves size reduction of drug to nanosize by milling the drug using a proprietary wet-milling technique. The nanocrystals of the drug are stabilized against agglomeration by surface adsorption on selected stabilizers, which are then incorporated into ODTs. Characteristics: It is used for poorly waterPorosity soluble is drugs. frequently It leads expressed to higher bioavailability in percentage and andreduction is given in dose, as: cost effective manufacturing process, conventional packaging due to exceptional durability and wide range of doses (up to 200 mg of drug per unit). %€ = (1 – Vp / Vb) X 100

11 Fast Dissolving Films Involves size reduction of drug to nanosize by milling the drug using a proprietary wet-milling technique. The nanocrystals of the drug are stabilized against agglomerationThe porosity by surface of adsorption powder onindicates selected stabilthe izers,types which of packaging are then incorporated a powder into ODTs. undergoes when subject to vibrations, when stored, or in tablet Characteristics: It is used for poorly water soluble drugs. It leads to higher bioavailability and reduction in dose, cost effective manufacturing process, conventionalmachine packaging when due passed to exceptional through durability hopper a ndor widefeed range frame. of doses (up to 200 mg of drug per unit).

12 (standard) Advantages: B. Evaluation of Tablets: All the formulated ODTs were  Low cost of production subjected to the following quality control tests (Shyamala et al,  Use of standard equipment/materials2002, Bradoo et al 2001, & Makino et al, 1993):

 High dose  Good physical resistance 1. Weight variation: The weight variation test is carried out in Disadvantages: order to ensure uniformity in the weight of tablets in a batch. First

 Significant effects of the size andthe hardnesstotal weight of the tablets of 20 on tablets disintegration from propertyeach formulation is determined

and the average is calculated. The individual weight of the each Advantages: Tableting (effervescent)  Use of standard equipment tablet is also determined to find out the weight variation. Table 9  High dose Good physical resistancedepicted USP Specification for uniformity of weight.  Pleasant effervescent mouth feel Disadvantages:  Operating in controlled low humidity  Need of totally impermeable blister

Tableting (Humidity Treatment) Advantages:  Good physical resistance.  Pleasant mouth feel Disadvantages:  Extra equipments for humidification and drying  Possible limitations in stability  High cost of production  Not suitable for moisture sensitive compounds  Fragile before humidity treatment

Compressibility index: The Compressibility Index of the blends is determined by compressibility index. Compressibility Index can be Table 5: Different Patented techniques for preparation of ODTs (Takagi et al, 2005 calculated by using following formula: & Modi et al, 2006)

Compressibility Index (%) = [(TD-BD) X 100] / TD] S. Technique Advantages Disadvantages No. Hausner’s ratio: A similar index to indicate the flow properties Quick dissolution, Self- Expensive process, poor 1 Zydis preserving and increased stability at higher Temperature can be defined by Hausner’s ratio. Hausner’s ratio can be bioavailability. and humidity. calculated by using following formula: 2 Orasolv Taste-masking is twofold, Low mechanical strength quick Dissolution. 3 Durasolv Higher mechanical Inappropriate with larger dose. Hausner’s ratio = (Tapped density x 100)/ (Poured density) strength than Orasolv, Good rigidity. Hausner’s ratio <1.25 – Good flow = 20% compressibility index 4 Flashtab Only conventional __ tableting technology 1.25 – Poor flow =33% compressibility index 5 Wow tab Adequate dissolution rate No significant change in and hardness. bioavailability Void Volume: The volume of the spaces is known as the void 6 Oraquick Faster and efficient -- production, appropriate volume “V” (Yoshio .et al) and is given by the formula for heat-sensitive drugs

7 Ziplet Good mechanical As soluble component V= Vb – Vp strength, satisfactory dissolves, rate of water

properties can be obtained diffusion in to tablet is Where, Vb = Bulk volume (volume before tapping) at high dose (450 mg) and decreased because of Vp = True volume (volume after tapping) high weight (850 mg). formation of viscous concentrated solution. Porosity: The porosity € of powder is defined as the ratio of void 8 FlashDose High surface area for High temperature required to volume to the bulk volume of the packaging. The porosity of the dissolution melt the matrix can limit the use of heat-sensitive drugs, powder is given by following formula: sensitive to moisture and humidity. €= Vb – Vp / Vp =1- Vp/Vb Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

Porosity is frequently expressed in percentage and is given as: Table 7: Angle of repose as an indication of powder flow properties.

S. No. Angle of Repose (°) Type of Flow %€ = (1 – Vp / Vb) X 100 1. < 20 Excellent The porosity of powder indicates the types of packaging a 2. 20 – 30 Good powder undergoes when subject to vibrations, when stored, or in 3. 30 – 34 Passable tablet machine when passed through hopper or feed frame. 4. > 34 Very Poor

B. Evaluation of Tablets: All the formulated ODTs were Table 8: Relationship between % compressibility index and flow ability. subjected to the following quality control tests (Shyamala et al, S. No. % compressibility index Type of Flow 2002, Bradoo et al 2001, & Makino et al, 1993): 1. 5-12 Excellent 2. 12-16 Good Weight variation: The weight variation test is carried out in order 3. 18-21 Fair to Passable 4. 23-35 Poor to ensure uniformity in the weight of tablets in a batch. First the 5. 33-38 Very Poor total weight of 20 tablets from each formulation is determined and 6. < 40 Very Very Poor the average is calculated. The individual weight of the each tablet Table 9: USP Specification for uniformity of weight. is also determined to find out the weight variation. Table 9 S.No. Average weight of Maximum % difference allowed depicted USP Specification for uniformity of weight. Tablets(mg)

Table 6: Patented technology and their branded products (Modi et al, 2006). 1 130 or less 10 2 130-324 7.5 S. No. Technology Process Patent owner Drugs Used 3 More than 324 5 involved (Brand name)

1 Zydis Lyophilization R.P.Scherer Inc. Loratidine (Claritin Reditab Hardness: The hardness of tablet is an indication of its strength. and Dimetapp Quick Dissolve) Measuring the force required to break the tablet across tests it. The 2 Quicksolv Lyophilization Jansen Cisapride force is measured in kg and the hardness of about 3-5 kg/cm2 is Pharmaceutical monohydrate (Propulsid considered to be satisfactory for uncoated tablets. Hardness of 10 Quicksolv), tablets from each formulation is determined by Monsanto hardness Risperidone (Risperdal M-tab) tester, Pfizer hardness tester etc. 3 Flashtab Lyophilization Ethypharm Ibuprofen (Nurofen Flashtab) Friability test: Friability is the loss of weight of tablet in the 4 Lyoc Multiparticulates Farmlyoc Phloroglucinol container due to removal of fine particles from the surface. Compressed Hydrate (Spasfon tablets Lyoc) Friability test is carried out to access the ability of the tablet to

5 Orasolv Compressed Cima Labs Inc. withstand abrasion in packaging, handling and transport. Roche Tablets (Tempra friabilator is employed for finding the friability of the tablets. Quicklets), Zolmitriptan Weigh the 20 tablets from each batch and place in Roche (Zolmig Repimelt friabilator that will rotate at 25 rpm for 4 minutes. Dedust the all

6 Durasolv Molding Cima Labs Inc. Hyoscyamine tablets and weigh again. The percentage of friability can be Sulfate (NuLev) calculated using the formula Zolmitriptan (Zolmig ZMT) % Friability = [(W1-W2)100]/W1 7 RapiTab Compressed Schwarz Pharma -- Tablets 8 Wow tab Compressed Yamanouchi Where, W1= Weight of tablet before test, W2 = Weight of tablet Molded Tablets Pharma (Gaster D) after test Technologies, Inc. Disintegration test: The USP disintegration apparatus contains six 9 Fast melt Molding Élan Corp. -- 10 Ziplets Molding Eurand Ibuprofen glass tubes that are “3 long, open at the top, and held against 10” (Cibalgina Due screen at the bottom end of the basket rack assembly. One tablet is Fast) 11 FlashDose Cotton-candy Fuisz Tramadol HCl placed in each tube and the basket rack is poisoned in 1 liter beaker process Technology Ltd. (Relivia Flash dose) of distilled water at 37± 2 °C, such that the tablets remain below the surface of the liquid on their upward movement and descend 12 Oraquick Micromask taste KV Pharm. Co., Hyoscyamine Masking Inc. Sulfate ODT not closer than 2.5cm from the bottom of the beaker.

13 Advatab Microcaps and Eurand AdvaTab diffuscap CR International cetrizine, Mechanical strength: Tablets should possess adequate mechanical Technology AdvaTab strength to bear shocks of handling in manufacturing, packaging Paracetamol and shipping. Crushing strength and friability are two important Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

parameters for the determination of mechanical strength. Crushing In-Vivo disintegration test: The test is carried out on 2 or 3 tablets Strength or Tablet Tensile strength is the force required to break a in the mouth and the time in second taken for complete tablet by compression in the radial direction, it is important to note disintegration of the tablet is measured. that excessive crushing strength significantly reduces the disintegration time. The crushing strength of the tablet is measured In-Vitro dissolution test: In-vitro dissolution study is performed by by using Pfizer hardness testers. Tensile strength for crushing (T) using USP Type II Apparatus (Paddle type) at 50 rpm. Phosphate is calculated using equation buffer pH 6.8, 900 ml is used as dissolution medium which maintained at 37±0.5°C. Withdraw aliquot of dissolution medium T= 2F / π*d*t (10 ml) at specific time intervals (2 min) and filter. The amount of drug dissolved is determined by suitable analytical technique. (Cirri et al, 2005) Where F is the crushing load, and d and t denote the diameter and thickness of the tablet respectively. Stability Studies: The optimized formulation of ODTs is subjected to stability study as per ICH guidelines to assess their stability with Uniformity of dispersion: Keep the Two tablets in 100ml water respect to their physical appearance and release characteristics. and stir gently for 2 minutes. The dispersion is passed through 22 meshes. The tablets will consider passing the test if no residue FUTURE POTENTIAL remained on the screen. These dosage forms may be suitable for the oral delivery Wetting time: The wetting time of the tablets is measure by using a of drugs such as and peptide-based therapeutics that have simple procedure. Place the five circular tissue papers of 10 cm limited bioavailability when administered by conventional tablets. diameter in a petridish containing 0.2% w/v solution (3ml). A These products usually degrade rapidly in the . Should tablet is carefully placed on the surface of the tissue paper. The next generation drugs are predominantly protein or peptide based, time require for develop blue color on the upper surface of the tablets may no longer be the dominant format for dosing such tablet is noted as the wetting time. moieties. Injections generally are not favored for use by patients unless facilitated by sophisticated auto-injectors. is one Water absorption ratio: A small piece of tissue paper folded twice good alternative system to deliver these drugs, but the increased is placed in a small petridish containing 6 ml of water. Put a tablet research into biopharmaceuticals so far has generated on the paper and the time required for complete wetting is predominantly chemical entities with low molecular weights. The measured. The wetted tablet is then reweighed. Water absorption developments of enhanced oral protein delivery technology by ratio, R is determine by using following formula ODTs which may release these drugs in the oral cavity are very R= 100 x Wa-Wb / Wb promising for the delivery of high molecular weight protein and peptide.

Table 10: Marketed Preparations of ODTs Where, Wb is the weight of tablet before water absorption S.No Name of the Product API Name of company Wa is the weight of tablet after water absorption 1. Imodium Lingual Imodium Janssen Taste/ Mouth sensation: Mouth-feel is critical, and patients should 2. Pepcidin Rapitab Pepcid - receive a product that feels pleasant. One tablet from each batch is 3. Mosid – MT Mosapride citrate. Torrent tested for the sensation by placing the tablet on the tongue. The 4. Calritin Reditabs Micronized Loratadine Schering plough healthy human volunteers are used for evaluation of mouth feel. Corp., USA 5. Nimulid – MD Nimesulide Panacea Taste evaluation is done by a panel of 5 members using time 6. Zyrof Meltab Rofecoxib - intensity method. Sample equivalent to 40 mg i.e. dose of drug is 7. Feldene Melt Pfizer put in mouth for 10 seconds and record taste instantly and then after 10 secs, 1, 2, 4 and 6 minutes. Volunteer’s opinion for the 8. Maxalt-MLT Rizatriptan Benzoate Merck 9. Pepcid ODT Famotidine Famotidine Merck taste is rated by giving different score values i.e. 0 = good, 1 = 10. Zyprexa Zydis Eli Lilly tasteless, 2 = slightly bitter, 3 = bitter, 4 = awful. 11. Zofran ODT Ondansetron GSK

12. Remeron Soltab Mirtazepine - In -Vitro disintegration test: In-vitro disintegration time is 13. Imodium Instant melts Loperamide HCl Janssen measured by dropping a tablet in a beaker containing 50 ml of 14. Romilast Montelukast Ranbaxy Sorenson’s buffer pH 6.8. Three tablets from each formulation are 15. Olanex instab Olanzapine Ranbaxy randomly selected and in vitro dispersion time is carried out. 16. Zomig ZMT and Zolmitriptan Astra Zeneca (Shirai et al, 1993) Rapimelt 17. Zotacet MD Cetrizine HCl Zota Pharma Journal of Applied Pharmaceutical Science 01 (04); 2011: 35-45

18. Valus Valdecoxib Glenmark commercialized to use this technology properly. Thus ODT may be 19. Torrox MT Rofecoxib Torrent developed for most of the available drugs in near future. 20. Rofaday MT Rofecoxib Lupin 21. Orthoref MD Rofecoxib Biochem REFERENCES 22. Nulev Hyoscyamine sulfate Schwarz Pharma Abdelbary G., Eouani C., Prinderre P., Joachim J., Reynier J., 23. Klonopin Wafers Clonazepam Roche Piccerelle P., Determination of the in vitro disintegration profile of rapidly 24. Kemstro Baclofen Schwarz Pharma disintegrating tablets and correlation with oral disintegration. Int.J. Pharm. 25. Zeplar TM Selegilline Amarin Corp., 2005, 292: 1-2; 29-41. London Allen LV., Wang B., Particulate Support Matrix for making a 26. Tempera Quiclets Acetaminophen Bristol myers rapidly dissolving tablet. 1997, US patent 5595761. Squibb, NY, USA Bansal AK., Improved excipients by solid-state manipulation. The 27. Febrectol Paracetamol Prographarm, Industrial Pharmacist. 2003, 31; 9-12. 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